CN101883763B - Intermediates and methods for the synthesis of halichondrin B analogs - Google Patents

Abstract

Methods of synthesis of intermediates useful in the synthesis of halichondrin B analogs are described.

Description

Intermediates and methods for the synthesis of halichondrin B analogs

related application

This application claims priority to U.S.S.N. 60/997,625, filed October 3, 2007, the entire contents of which are hereby incorporated by reference.

Background of the invention

The present invention relates to methods for synthesizing halichondrin B and its analogues having pharmaceutical activity such as anticancer or antimitotic (mitosis arrest) activity. B-1939 (also known as E7389 or eribulin), a halichondrin B analog, has been reported to be effective in the treatment of cancer and other proliferative diseases including melanoma, fibrosarcoma, leukemia, colon cancer , ovarian cancer, breast cancer, osteosarcoma, prostate cancer, lung cancer and ras-transformed fibroblasts.

Halichondrin B is a structurally complex natural marine product containing multiple chiral centers on an extended carbon framework. Due to the limited supply of halichondrin B from natural sources, methods for the synthesis of halichondrin B are of value for exploiting the full pharmaceutical potential of halichondrin B analogs. In 1992, (Aicher, T.D. et al., J. Am. Chem. Soc. 114: 3162-3164) disclosed methods for the synthesis of halichondrin B analogs. Methods for the synthesis of halichondrin B analogs including B-1939 are described in WO2005/118565 (EISAI COMPANY, LTD.). The method described in WO2005/118565 has several practical advantages over that described by Aicher, including but not limited to the discovery of several crystalline intermediates that can improve quality control, reproducibility and throughput. Despite these advantages, there are several throughput-limiting chromatographic purification methods involving the C14-C26 fragment in particular. For example, the C14-C26 fragment contains 4 chiral centers at C17, C20, C23 and C25, and chromatography is required to control the quality of this fragment. More specifically, the C25 chiral center moiety is not highly selective, and its selectivity cannot actually be enhanced due to the absence of crystalline intermediates at later stages in the synthesis of C14–C26.

More efficient, less costly, and more practical methods are needed for the synthesis of halichondrin B analogs, particularly B-1939.

brief description

The present invention relates to the synthesis of halichondrin B analogs such as B-1939 from (-)-quinic acid according to the method exemplified in Scheme 1 below. This method introduces a number of novel crystalline intermediates that can significantly improve the stereochemical quality of the synthesized compounds and reduce the need for chromatographic steps. Unlike the methods described above, the method claimed in the present invention is actually more suitable for pharmaceutical production.

The present invention also relates to the novel intermediates disclosed herein.

plan 1

WO2005/118565 discloses a method for preparing halichondrin B analogues such as B-1939, said method comprising the following synthetic routes: (1) preparing a compound of formula Ia from (-)-quinic acid, (2) preparing from compound AG B-1939. Both synthetic routes are suitable for use in the methods of the present invention, which are incorporated herein by reference.

The method of the present invention differs from the method disclosed in WO2005/118565 in the synthesis of compound AH from compound AA. In particular, the present invention discloses the generation of the C25 chirality marked with an asterisk (*) in the related compounds in Scheme 1 by equilibrating and selectively crystallizing the desired C25 isomer via an α-methylated nitrile. A highly effective approach to the sex center. In the method described in WO2005/118565, compound AH is synthesized by adding a methyl group to compound AG, as shown above. This reaction generates the C25 chiral center. The product of the reaction is a mixture of diastereoisomers in each possible configuration around the chiral center. As disclosed in WO2005/118565, Compound AH can be partially isolated from diastereomeric mixtures by chromatography; however, the remaining diastereomers of Compound AH can lead to unwanted impurities in subsequent reaction steps, said Impurities can only be removed by additional purification operations.

Different from the aforementioned methods for synthesizing halichondrin B analogues, the method of the present invention involves the formation of the C25 chiral center in the early stage of the synthesis of compound AH. Several methylated intermediates, including Compound AD and Compound AF, were crystallizable. Substantially diastereomerically pure compositions comprising Compound AH can be prepared by crystallizing one or more methylated intermediates using the methods of the present invention, for example, Compound AC can be methylated to give Compound AD. When compound AD was formed, the C25 chiral center was created, the same chiral center discussed for compound AH. When this reaction occurs, a diastereomeric mixture will be produced around that chiral center in each possible stereoisomeric configuration. Despite the low stereoselectivity of methylation itself, surprisingly, the desired diastereomer of compound AD can be crystallized stereoselectively. Furthermore, the undesired C25 stereoisomer can be epimerized under the crystallization conditions of the desired C25 stereoisomer. Therefore, crystallization-induced dynamic resolution (CIDR) can improve the yield and quality of the C25 stereoisomer.

Several other intermediates produced in the synthetic route from compound AD to compound AH can also be crystallized from the reaction mixture, resulting in a composition of compound AH of higher purity than can be obtained by previously disclosed methods. In particular, compound AF is a crystalline compound, whereas the corresponding unmethylated compound AE needs to be purified by chromatography. Compound AF can be synthesized from compound AD, or it can be synthesized by methylation of compound AE.

Removal of the chromatography step from the process used for the synthesis of the halichondrin B analogs significantly increased product yield and reproducibility while reducing cost and production time. This method also solves the problem of splitting chiral centers at a fairly early point in the preparation process, even as early as in the preparation of Compound AH and Compound AI. B-1939 was synthesized from compound AI using the method as described in WO/2005/118565.

In one embodiment, the present invention relates at least in part to a process for obtaining a substantially diastereomerically pure composition comprising a compound of formula (I). The process comprises crystallizing a compound of formula (I) from a diastereomeric mixture under suitable crystallization conditions to obtain a substantially diastereomerically pure composition comprising a compound of formula (I). The compound of formula (I) is:

in:

z is a single bond or a double bond, with the proviso that when z is a ^double bond, X2 is C and ^Y1 is hydrogen; with the proviso that when z is a single bond, X2 is ^CH or O;

^X1 is O, S or CN, with the proviso that when ^X1 is CN or S, X2 is O ^;

Y ¹ is halide, hydrogen or OL ² , or when X ² is O, Y ¹ is absent; and

L ¹ and L ² are independently selected from hydrogen and a protecting group, or L ¹ and L ² together are a protecting group, with the proviso that when X ¹ is CN, L ¹ is absent; and salts thereof. In addition to compounds of formula (I), the present invention also relates to compositions of compounds of formula (I) which are substantially free of diastereomers.

In another embodiment, the present invention also relates to a process for preparing a diastereomerically pure composition of a compound of formula (Ib) from a compound of formula (Ia), wherein the compound of formula (Ia) is:

Compounds of formula (Ib) are:

wherein L ^1a and L ^{1b are} independently selected from hydrogen and a protecting group, or L ^1a and L ^1b together are a divalent protecting group, provided that when L ^1a of formulas (Ia) and (Ib) are the same and formulas (Ia) and The same applies to L ^1b of (Ib). When L ^1a or L ^1b is a protecting group, it is preferably selected from C ₁ -C ₆ alkyl ethers, aryl (C ₁ -C ₆ ) alkyl ethers, silyl (C ₁ -C ₁₀ ) ethers, C ₁ -C ₆ alkyl esters, cyclic C ₁ -C ₆ acetals, cyclic C ₂ -C ₇ ketals and cyclic carbonates. The method comprises reacting a compound of formula (Ia) under alkylation conditions to obtain a mixture comprising a compound of formula (Ib) and its diastereoisomers; A compound of formula (Ib).

In another embodiment, the present invention relates at least in part to a process for obtaining a substantially diastereomerically pure composition comprising a compound of formula (II). The process comprises crystallizing a compound of formula (II) from a mixture of diastereomers under a second suitable crystallization condition to obtain a substantially diastereomerically pure combination comprising a compound of formula (II) thing. The compound of formula (II) is:

in:

c is a single bond or a double bond, provided that when c is a double bond, m is 0, and Y ³ is O or CHCO ₂ -L ³ , provided that when c is a single bond, m is 0 or 1 and Y ³ is CH ₂ OL ³ , CH ₂ CO ₂ -L ³ or CH ₂ CH ₂ OL ³ ;

Y ² is C ₁ -C ₇ sulfonate, OL ⁴ or halide;

L ⁴ is hydrogen or a protecting group; and

^L3 and ^L5 are each independently hydrogen or a protecting group, or ^L3 and ^L5 together are a protecting group, or a salt thereof. In addition to compounds of formula (II), the present invention also relates to compositions of compounds of formula (II) which are substantially free of diastereomers.

In yet another embodiment, the present invention also relates to compounds of compound formula (III) and salts thereof:

Wherein: L ⁶ is hydrogen or a protecting group.

In yet another embodiment, the present invention also relates to compositions comprising a compound of formula (IIIa):

Each of L ^6a , L ^6b and L ^6c is a protecting group, or a salt thereof, wherein the composition is substantially free of diastereomers.

In addition, the present invention also relates to a compound selected from formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III) and Compositions of compounds of (IIIa).

detail

The present invention relates at least in part to methods and intermediates for preparing and crystallizing intermediates and other compounds useful in the synthesis of halichondrin B and analogs thereof.

A. Definition

In order to make the present invention easier to understand, some terms are first defined. Other definitions are set forth throughout the detailed description.

The term "acetyl" refers to acyl (such as -C(=O)-CH ₃ ) and C ₁ -C ₈ alkyl substituted carbonyl (such as -C-(=O)-(C ₁ -C ₇ )alkyl )). Preferably, the acetyl group is an acyl group.

The term "alkyl" refers to a saturated hydrocarbon group with one or more carbon atoms, including straight-chain alkyl (such as methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.), cyclic alkyl (or "cycloalkyl" or "cycloaliphatic" or "carbocyclic" group) (such as cyclopropyl, cyclopentyl, cyclohexyl, etc.), branched chain alkyl (isopropyl, tert-butyl, sec-butyl , isobutyl, etc.) and alkyl-substituted alkyl (such as alkyl-substituted cycloalkyl and cycloalkyl-substituted alkyl). The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups similar to alkyl, but containing at least one carbon-carbon double bond or triple bond, respectively.

The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentyloxy. The alkoxy group may be linear or branched. Preferred alkoxy groups include methoxy.

The term "heterocyclyl" refers to a closed ring structure similar to a carbocyclic group, wherein one or more carbon atoms in the ring are elements other than carbon, such as nitrogen, sulfur or oxygen. A heterocyclyl group can be saturated or unsaturated. Additionally, heterocyclic groups such as pyrrolyl, pyridyl, isoquinolyl, quinolinyl, purinyl and furyl may be of aromatic nature, in which case they may be referred to as "heteroaryl" or "heteroaryl" Heteroaromatic" group. Examples of heterocyclic groups include, but are not limited to, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, benzo Oxazole, benzobisoxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzo Furan, azapurine or indolizine.

The term "amine" or "amino" refers to an unsubstituted or substituted moiety of the formula -NR ^a R ^b , wherein R ^a and R ^b are each independently hydrogen, alkyl, aryl, or heterocyclyl, or R ^a and R ^b together with the nitrogen atom connecting them form a cyclic moiety having 3-8 atoms in the ring. Thus, unless otherwise stated, the term amino includes cyclic amino moieties such as piperidinyl or pyrrolidinyl.

With respect to connectivity, "arylalkyl", eg, is an alkyl group substituted with an aryl group (eg, phenylmethyl (ie, benzyl)). An "alkylaryl" moiety is an aryl group substituted with an alkyl group (eg, p-methylphenyl (ie, p-tolyl)). Thus, the term imidazolyl-alkyl refers to an alkyl group substituted with an imidazolyl moiety.

The term "sulfonate" refers to a moiety of the formula: R-SO2 _- O-, wherein R is _C1 - _C4 alkyl or _C6 - _C8 aryl. Examples of sulfonate esters include methanesulfonate (mesylate), trifluoromethanesulfonate (triflate), p-toluenesulfonate (tosylate) and benzenesulfonate (bensylate ).

As used in the specification and figures, optional single/double bonds are indicated by a solid line together with a second dashed line, which means that the covalent linkage between two carbon atoms can be either a single bond or a double bond. For example, the following structure:

Can represent butane or butene.

The term "protecting group" refers to a hydroxyl, thiol, carboxylic acid group or other functional group that can be cleaved from a compound to obtain protection as desired by those skilled in the art. In general, protecting groups are selected to resist cleavage during reactions against other parts of the molecule. Acid-labile (eg, cleavage in the presence of an acid), base-labile (eg, cleavage in the presence of a base), or other selectively cleavable protecting groups may be selected. Protecting groups are well known to those skilled in the art. Examples of suitable protecting groups can be found in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, Inc.

Examples of protecting groups include, but are not limited to, C ₁ -C ₁₂ alkylcarbonyl, C ₁ -C ₆ alkyl, C ₁ -C ₁₅ alkylsilyl moieties (such as can form when bonded to an adjacent oxygen part of alkylsilyl ether), aryl(C ₁ -C ₆ )alkyl, carbonate and C ₁ -C ₆ alkoxy-(C ₁ -C ₆ )alkyl (such as methoxymethyl ).

Examples of C ₁ -C ₁₀ alkylsilyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylmethylsilyl A silyl group or a tripropylsilyl group (such as trimethylsilyl ether, triethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyl diphenyl silyl ether or triisopropyl silyl ether). Preferably, the alkylsilyl protecting group is tert-butyldimethylsilyl ether.

Examples of C ₁ -C ₆ alkyl protecting groups include methyl and tert-butyl (such as methyl ether and tert-butyl ether when attached to an adjacent oxygen atom).

Examples of aryl(C ₁ -C ₆ )alkyl protecting groups include 3,4-dimethoxybenzyl, p-methoxybenzyl, benzyl or trityl (such as when adjacent oxygen When the atoms are linked to form 3,4-dimethoxybenzyl ether, p-methoxybenzyl ether, benzyl ether or trityl ether).

Compounds with two or more groups to be protected (eg, hydroxyl and/or thiol) can be protected together with protecting groups that are attached to both the hydroxyl and/or thiol to be protected. These protecting groups are also referred to herein as "divalent protecting groups". Examples of divalent protecting groups that can protect two hydroxyl and/or mercapto groups include, but are not limited to, C ₁ -C ₆ acetals, C ₂ -C ₆ ketals, and cyclic carbonates. Examples of cyclic protecting groups include, but are not limited to, acetonide, benzylidine, and, preferably, cyclohexylidine. Examples of protecting groups that can protect two hydroxyl groups and/or mercapto groups include those listed below. Arrows indicate the moiety on the compound that is attached to a hydroxyl or sulfhydryl group:

The term "acceptable salt" refers to salts of compounds of the present invention that are acceptable to the methods of the present invention, such as intermediates in the synthesis of halichondrin B analogs.

The compounds of the present invention are acidic in nature and form various base salts. Chemical bases useful in the preparation of acceptable base salts of compounds of the invention which are acidic in nature are those chemical bases which form base salts with said compounds. Such base salts include, but are not limited to, those derived from such pharmaceutically acceptable cations as alkali metal cations (such as potassium and sodium) and alkaline earth metal cations (such as calcium and magnesium), ammonium or water-soluble amine addition salts such as N- Methylglucamine - (Meglumine) and base salts of lower alkanolammonium and other pharmaceutically acceptable organic amines. Base addition salts of compounds of the invention which are acidic in nature can be formed with cations by conventional methods.

The term "antisolvent" includes organic solvents in which the compound of interest is substantially insoluble. Examples of antisolvents for the compound of formula (II) of the present invention include nonpolar organic solvents such as heptane.

The term "alkylating agent" refers to an agent that can add an alkyl group, preferably a methyl group, to certain organic compounds described herein, including but not limited to compounds of formula (Ia). Preferably, the alkylating agent is a C ₁ -C ₄ alkyl halide (preferably MeI) or a sulfonate.

The term "suitable alkylation conditions" refers to conditions selected to carry out the alkylation reaction. These conditions include aprotic solvents such as tetrahydrofuran, toluene or tert-butyl methyl ether, and bases such as metal amides or metal alkoxides. Examples of bases that can be used in the alkylation conditions include, but are not limited to, LDA, KHMDS, and potassium tert-butoxide.

The expression "suitable crystallization conditions" refers to conditions selected to crystallize the desired diastereomer of a particular compound, preferably a compound of formula (I) or (Ib). Examples of solvent systems that can be used to carry out this crystallization include, but are not limited to, heptane and mixtures of heptane with one or more co-solvents such as, but not limited to, tert-butyl methyl ether and isopropanol. The ratio of heptane to tert-butyl methyl ether or isopropanol is chosen to crystallize the desired diastereomer. The ratio may range from about 5:1 to about 3:1, preferably about 4:1. The appropriate conditions may also include the addition of a base. Examples of the base include C ₁ -C ₆ alkoxides (such as tert-butoxide or isopropoxide). Alternatively, other solvent systems may also be used, such as combinations of protic solvents and antisolvents.

The expression "a second suitable crystallization condition" refers to conditions selected to crystallize the desired diastereomer of a particular compound, preferably a compound of formula (II) or (IIa). A second example of suitable crystallization conditions for the crystallization of a compound of formula (II) and/or (IIa) involves dissolving the compound in a polar solvent such as MTBE and optionally adding an antisolvent to precipitate the compound.

The term "contacting" refers to any interaction between two or more compounds that produces a chemical reaction, such as, but not limited to, the creation or cleavage of one or more chemical bonds.

The expression "mixture of diastereoisomers" refers to a composition comprising two or more diastereoisomers.

The term "protic solvent" refers to a solvent that contains dissociable H ⁺ or groups that can form hydrogen bonds, such as hydroxyl or amino groups. Examples thereof are water, methanol, ethanol, formic acid, hydrogen fluoride and ammonia water. Preferred protic solvents include alcohols such as isopropanol.

The phrase "substantially diastereomerically pure composition" means that the ratio of the specified compound to the chiral center marked with an asterisk in Scheme 1 is at least about 8:1 or higher, at least about 10 :1 or higher, at least about 15:1 or higher, at least about 20:1 or higher, or, preferably, at least about 30:1 or higher. Multiple kinetic or crystallization-induced dynamic resolutions can be employed to increase diastereomeric purity.

The phrase "substantially without chromatography" means that 4 steps or less, 3 steps or less, 2 steps or less, 1 step or less or no chromatography steps are used. Preferably, the term refers to synthetic methods that do not require a preparative HPLC step.

This document uses certain abbreviations and abbreviations. The definitions of these abbreviations and abbreviations are listed below:

ACN acetonitrile

AcOH acetic acid

Dynamic resolution induced by CIDR crystallization

DBU Diazabicycloundecane

DCM dichloromethane

DIBAL diisobutyl aluminum hydride

DME dimethoxyethane

DMF Dimethylformamide

ESI electron spin injection (Electronspin injection)

Et ₃ N triethylamine

Ethyl EtOAc

EtOH ethanol

FDA Food and Drug Administration

HPLC high pressure liquid chromatography

IPA isopropyl alcohol

ⁱ Pr ₂ NEt Diisopropylethylamine

KHMDS potassium hexamethyldisilazide (potassium-

hexamethyldisilazane)

Potassium KO ^t Bu tert-butoxide

Lithium diisopropylamide LDA

LRMS low resolution mass spectrometry

MeI iodomethane

MeOH Methanol

MsCl Methanesulfonyl Chloride (Methanesulfonyl Chloride; CH ₃ SO ₂ Cl)

MTBE methyl tert-butyl ether

MsO-Methanesulfonate (Methanesulfonate)

NaOEt sodium ethoxide

NaOMe sodium methoxide

NBSN-Bromosuccinimide

NISN-Iodosuccinimide

NMR nuclear magnetic resonance

Ph ₃ P triphenylphosphine

TBDPSCl tert-butyldiphenylsilyl chloride

TBME tert-butyl methyl ether

TBS tert-butyldimethylsilyl

TBSCl tert-butyldimethylsilyl chloride

TBSOTf tert-butyldimethylsilyl trifluoromethanesulfonate

^t BuOK Potassium tert-butoxide

TEA triethylamine

TESOTf Triethylsilyl Trifluoromethanesulfonate

TsCl Toluenesulfonyl Chloride (p-Toluenesulfonyl Chloride)

TfO-Trifluoromethanesulfonate (Trifluoromethanesulfonate)

Tf ₂ O trifluoromethanesulfonic anhydride (CF ₃ SO ₂ ) ₂ O

TsO-toluenesulfonate (p-toluenesulfonate)

THF Hydrofuran

TsOH p-toluenesulfonic acid

TosMIC tosylmethyl isocyanide

Trt trityl (triphenylmethyl)

B. Compound

In one embodiment, the present invention relates to compounds of formula (I) and salts thereof:

in:

z is a single bond or a double bond, with the proviso that when z is a ^double bond, X2 is C and ^Y1 is hydrogen; with the proviso that when z is a single bond, X2 is ^CH or O;

^X1 is O, S or CN, with the proviso that when ^X1 is CN or S, X2 is O ^;

Y ¹ is halide, hydrogen or OL ² , or when X ² is O, Y ¹ is absent; and

L ¹ and L ² are independently selected from hydrogen and a protecting group, or L ¹ and L ² together are a protecting group, with the proviso that when X ¹ is CN, L ¹ is absent; the present invention also relates to compounds of formula (I).

In one embodiment, each of L ¹ and/or L ² is independently a silyl ether, a C ₁ -C ₈ alkyl ether, an acyl group (—C(=O)CH ₃ ) or an acetyl group. Preferably, X ¹ is oxygen.

Preferably, when Y ¹ is OL ² , L ¹ and L ² may represent the same protecting group attached to the molecule through O of X ² and X ¹ . Examples of such protecting groups include, but are not limited to, cyclic C ₁ -C ₆ acetals, cyclic C ₂ -C ₆ ketals, and cyclic carbonates. ^In additional embodiments, L1 and L2 are linked to ^a single divalent protecting group. Examples of divalent protecting groups include acetonides, benzylidines, and preferably, cyclohexylidine. ^In certain embodiments, when L1 and L2 are ^both protecting groups, L1 and ^L2 can form together ^a pentane, hexane or pyran ring and be connected to X1 and ^X2 through ^a single carbon atom . Preferably, when Y ¹ is OL ² ; X ¹ is O or S; L ¹ and L ² together form a protecting group, which is a C ₄ -C ₇ alkyl ring, and one member on the ring is connected to the O of OL ² and ^X1 are covalently linked.

In ^one embodiment, X2 is ^CH , ^Y1 is ^OL2 , and X1 is O.

In another embodiment, when ^Y1 is halide, it is fluoride, chloride, iodide, or, preferably, bromide. ^In yet another embodiment, L is acetyl.

In another embodiment, Y is ^hydrogen and X is C when z is a double bond. In yet another embodiment, X ¹ is oxygen and L ¹ is selected from the group consisting of C ₁ -C ₆ alkyl ethers, aryl(C ₁ -C ₆ ) alkyl ethers, C ₁ -C ₆ esters and silyl ( C ₁ -C ₁₀ ) Protecting group for ether (when attached to X ¹ ).

^In yet another embodiment, when z is a single bond, X2 is oxygen. ^In yet another embodiment, L1 is hydrogen. In yet another embodiment, L ¹ is a protecting group selected from glycoside, C ₁ -C ₆ alkyl, C ₁ -C ₆ acetyl and C ₁ -C ₆ ester.

Preferably, the compound of formula (I) is a compound of formula (Ib):

wherein L ^1a and L ^1b are hydrogen, independently selected protecting groups or together a single divalent protecting group.

In additional embodiments, L ^1a and L ^1b are each selected from C ₁ -C ₆ alkyl ethers, aryl (C ₁ -C ₆ ) alkyl ethers, silyl (C ₁ -C ₁₀ ) ethers, Protecting groups for C ₁ -C ₆ alkyl esters, cyclic C ₁ -C ₆ acetals, cyclic C ₂ -C ₇ ketals and cyclic carbonates.

In a further embodiment, the present invention is directed to a composition comprising a compound of formula (Ib), wherein said composition is substantially diastereomerically pure. In additional embodiments, the ratio of the compound of formula (Ib) to the compound having the opposite stereochemistry at the chiral center marked with an asterisk is at least about 8:1 or greater, at least about 20:1 or greater High, or, preferably, at least about 30:1 or higher.

In other embodiments, the compound of formula (I) is selected from:

Compound AD Compound AJ Compound AK

Compound AL Compound AM

or its salt.

In another embodiment, the present invention relates to a compound of formula (II) or a salt thereof:

in:

c is a single bond or a double bond, provided that when c is a double bond, m is 0, and Y ³ is O or CHCO ₂ -L ³ , provided that when c is a single bond, m is 0 or 1, and Y ³ is CH ₂ OL ³ , CH ₂ CO ₂ -L ³ or CH ₂ CH ₂ OL ³ ;

Y ² is C ₁ -C ₇ sulfonate, OL ⁴ or halide;

L ⁴ is hydrogen or a protecting group; and

^L3 and ^L5 are each independently hydrogen or a protecting group, or ^L3 and ^L5 together are a protecting group.

Examples of ^Y2 include halides, such as fluoride, chloride, bromide, or preferably, iodide. In another embodiment, Y ² is OL ⁴ . Examples of ^L4 include hydrogen. In another embodiment, c is a double bond. When c is a double bond, examples of Y ³ include CHCO ₂ -L ³ . Examples of L ³ groups include C ₁ -C ₆ alkyl groups such as methyl.

In another embodiment, c is a single bond. When c is a single bond, examples of Y ³ include CH ₂ CH ₂ —OL ³ . In additional embodiments, L ³ and L ⁵ can be linked to form a cyclic C ₁ -C ₆ acetal or a cyclic C ₂ -C ₇ ketal.

In other embodiments, Y ³ is CH ₂ CO ₂ -L ³ and L ³ is C ₁ -C ₁₀ alkyl, C ₄ -C ₁₀ aryl-C ₁ -C ₆ alkyl or C ₄ -C ₁₀ Aryl. In yet another embodiment, ^Y2 is a halide, such as iodide.

In additional embodiments, the present invention is directed to compositions comprising a compound of formula (II), wherein said compositions are substantially diastereomerically pure. In other embodiments, the ratio of the compound of formula (II) to the compound having the opposite stereochemistry at the chiral center marked with an asterisk is at least about 8:1 or higher, at least about 20:1 or higher , or, preferably, at least about 30:1 or higher.

In yet another embodiment, the compound of formula (II) is selected from:

Compound AN Compound AO Compound AF

Compound AP, and Compound AQ

or its salt.

The present invention also relates to substantially diastereoisomer-free compositions comprising the compounds shown above.

In additional embodiments, the present invention also relates to compounds of formula (IIa):

In other embodiments, the compounds of formula (IIa) are substantially free of diastereoisomers, such as compounds having the opposite stereochemistry at the chiral carbon marked with an asterisk in the above formula. In one embodiment, the present invention relates to substantially diastereomerically pure compositions comprising a compound of formula (IIa) wherein the compound of formula (IIa) has the opposite stereochemistry at the chiral center marked with an asterisk. The ratio of compounds is at least about 8:1 or higher, at least about 20:1 or higher, or, preferably, at least about 30:1 or higher.

Compounds of formula (IIa) are of particular importance since they may be crystalline, the corresponding non-methylated intermediates are not and require purification by chromatography. The present invention also relates to compounds of formula (IIa) in crystalline form.

In another embodiment, the present invention relates to a compound of formula (III) or an acceptable salt thereof:

Wherein: L ⁶ is hydrogen or a protecting group. In one embodiment, the present invention relates to substantially diastereomerically pure compositions comprising a compound of formula (III), wherein the compound of formula (III) has the opposite stereochemistry to the compound at the chiral center marked with an asterisk The ratio of at least about 8:1 or higher, at least about 20:1 or higher, or, preferably, at least about 30:1 or higher.

In additional embodiments, L ⁶ is hydrogen, or when taken with the oxygen attached thereto, a silyl C ₁ -C ₁₀ ether. Examples of the silyl C ₁ -C ₁₀ ethers include, but are not limited to, trimethylsilyl ether, triethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenyl Silyl ether or triisopropylsilyl ether.

In other embodiments, the compound of formula (III) is:

Compound AR Compound AH

The present invention also relates to substantially diastereoisomer-free compositions comprising the compounds shown above.

In another embodiment, the present invention relates to a compound of formula (IIIa) or a salt thereof:

wherein L ^6a , L ^6b and L ^6c are each a protecting group. In a further embodiment, the present invention is directed to a composition comprising a compound of formula (IIIa), wherein said composition is substantially free of diastereoisomers (as indicated by the asterisked symbol in formula (IIIa) above). Compounds with opposite stereochemistry at the sex center).

The present invention also relates at least in part to compounds of formula (Id): or salts thereof:

wherein L ^1a and L ^{1b are} independently selected from hydrogen and a protecting group, or L ^1a and L ^1b together are a divalent protecting group.

c. method

In one embodiment, the present invention relates to a process for obtaining a substantially diastereomerically pure composition comprising a compound of formula (I). The process comprises crystallizing a compound of formula (I) from a mixture of diastereomers under suitable crystallization conditions to obtain a substantially diastereomerically pure composition comprising a compound of formula (I).

The mixture of diastereoisomers is preferably a mixture of a compound of formula (I) and a compound of formula (Ie), wherein the compound of formula (Ie) is:

In one embodiment, a substantially diastereomerically pure composition comprises a ratio of a compound of formula (I) to a compound of formula (Ie) of at least about 8:1 or greater, at least about 10:1 or greater High, at least about 20:1 or higher, or, preferably, at least about 30:1 or higher. In order to increase the diastereomeric purity of the compound of formula (I), said compound may be recrystallized again under similar suitable conditions.

Appropriate crystallization conditions are chosen to enable crystallization of the desired diastereomer. Examples of solvent systems that can be used to perform this crystallization include, but are not limited to, heptane/tert-butyl methyl ether and heptane/isopropanol. Suitable conditions may also include the addition of a base. Examples of the base include C ₁ -C ₆ alkoxides (such as tert-butoxide or isopropoxide).

Alternatively, other solvent systems may also be used, such as combinations of protic solvents (eg, ethanol, isopropanol) and antisolvents (eg, non-polar organic solvents, such as heptane).

In a further embodiment, the present invention also relates to a method of synthesizing a compound of formula (Ib) from a compound of formula (Ia) by contacting a compound of formula (Ia) with an alkylating agent under suitable alkylation conditions. The compound of formula (Ia) is:

The compound of formula (Ib) is:

wherein L ^1a and L ^{1b are} independently selected from hydrogen and a protecting group, or L ^1a and L ^1b together are a divalent protecting group, provided that L ^1a of formulas (Ia) and (Ib) are the same, and formula (Ia ) and L ^1b of (Ib) are the same. The method comprises reacting a compound of formula (Ia) under alkylation conditions to generate a mixture comprising a compound of formula (Ib) and its diastereoisomers; and crystallizing out the compound of formula ( Ib) Compounds.

In order to increase the diastereomeric purity of the compound of formula (Ib), the compound may be recrystallized again under similar appropriate conditions. Preferably, after two or more crystallizations, the ratio of the compound of formula (Ib) in the mixture of diastereomers to the compound having the opposite stereochemistry at the chiral center marked with an asterisk in formula (Ib) is at least about 8 :1 or higher, at least about 10:1 or higher, at least about 20:1 or higher, or at least about 30:1 or higher.

In yet another embodiment, the present invention also relates at least in part to a process for obtaining a substantially diastereomerically pure composition comprising a compound of formula (I). The method comprises contacting a diastereomeric mixture with a base at an appropriate temperature to obtain a substantially diastereomeric pure composition comprising a compound of formula (I).

Examples of bases that can be used in the method include bases known in the art, such as amide bases, metal alkoxides, and KHMDS. The amount of the base may be any amount that yields the desired diastereomer. Preferably, the amount of the base is less than the stoichiometric amount (eg, less than one equivalent). In yet another embodiment, the suitable temperature is less than about -30°C. In additional embodiments, the compound of formula (I) is a compound of formula (Ib).

If the stereocenter requires kinetic resolution, formula (I) or (II) can be treated with a substoichiometric amount of a strong base (such as an amide base, such as KHMDS) at low temperature (such as below about -30°C) compound of. Once the reaction has occurred, the compound of formula (I) or (II) can be isolated from a suitable crystallization solvent system and recrystallized. Examples of useful solvent systems include, but are not limited to, heptane, heptane/t-butyl methyl ether, and heptane/isopropanol.

Alternatively, crystallization-induced dynamic resolution (CIDR) can also be used to increase the diastereomeric purity of compounds of formula (I) and/or (II). For example, compounds of formula (I) and/or (II) are treated with a weak base such as an alkoxide (eg potassium tert-butoxide or potassium isopropoxide) in an appropriate crystallization solvent system. Examples of suitable solvent systems for crystallization that yield purified compounds of formula (I) or (II) at non-low temperatures include combinations of protic solvents such as isopropanol and antisolvents such as heptane.

In another embodiment, the present invention relates to a process for obtaining a substantially diastereomerically pure composition comprising a compound of formula (II). The process comprises crystallizing a compound of formula (II) from a mixture of diastereomers under suitable crystallization conditions to obtain a substantially diastereomerically pure composition comprising a compound of formula (II).

In one embodiment, the composition comprises a ratio of compound of formula (II) to compound of formula (IIb) of at least about 8:1 or higher, at least about 10:1 or higher, at least about 20:1 1 or higher, or, preferably, at least about 30:1 or higher. Compounds of formula (IIb) are:

In order to increase the diastereomeric purity of the compound of formula (II), the compound can be recrystallized again under similar suitable conditions.

In another embodiment, the present invention also relates to a process for the synthesis of compounds of formula (Ia) from formula (Ib). The method comprises selectively crystallizing out a compound of formula (Ib) under appropriate crystallization conditions; reacting a compound of formula (Ib) under appropriate conditions to obtain a compound of formula (IIa). Preferably, substantially no chromatography is employed to obtain the compound of formula (IIa). After diastereomeric purification by recrystallization, the compound of formula (Ib) can be reacted under appropriate conditions to obtain the compound of formula (IIa). Alternatively, said suitable conditions may comprise dissolving the crystalline compound of formula (Ib) in a solvent prior to reacting it under suitable conditions to give the compound of formula (IIa).

Suitable conditions for the synthesis of compounds of formula (Ha) from compounds of formula (Ib) are described in Schemes 5, 6, 8, 9 and 10, for example. Methods for the selective crystallization of compounds of formula (I) or formula (Ib) from mixtures of diastereomers have been described above.

The present invention also relates at least in part to methods of synthesizing compounds of formula (Ilia) from compounds of formula (IIa). The process comprises crystallizing out a compound of formula (IIa) under a second suitable crystallization condition; reacting a compound of formula (IIa) under suitable conditions to obtain a compound of formula (IIIa).

A second example of suitable crystallization conditions for crystallizing a compound of formula (IIa) involves dissolving the compound in a polar solvent such as MTBE, optionally with the addition of an antisolvent to precipitate the compound. Examples of useful antisolvents include heptane. Preferably, after crystallization, the compound of formula (IIa) is reacted under suitable conditions to form the compound of formula (Ilia).

In another embodiment, the present invention also relates to a process for the synthesis of formula (Ilia) from a compound of formula (Ib). The process comprises selectively crystallizing out a compound of formula (Ib) under appropriate crystallization conditions; reacting a compound of formula (Ib) under appropriate conditions to obtain a compound of formula (Ilia). Preferably, compounds of formula (Ilia) are prepared substantially without chromatography.

After diastereomeric purification by recrystallization, the compound of formula (Ib) can be reacted under appropriate conditions to obtain the compound of formula (IIIa). Alternatively, the suitable conditions may include dissolving the crystalline compound of formula (Ib) in a solvent prior to reacting it under suitable conditions to form the compound of formula (Ilia).

In another embodiment, the present invention is directed to a process for the synthesis of compounds of formula (IV). The process comprises crystallization of a compound of formula (Ib) from a mixture of diastereomers under appropriate crystallization conditions as described above; reacting the selectively crystallized compound of formula (Ib) with a suitable reagent to synthesize the compound of formula ( IV) compounds. The compound of formula (IV) is:

wherein each of L ^7a , L ^7b , L ^7c , L ^7d and L ^7e is independently a protecting group or hydrogen. Examples of L ^7a include phenyl. Examples of L ^7b include methyl. Examples of L ^7c and L ^7d include TBS. Examples of L ^7e include hydrogen.

Suitable reagents that can be used to synthesize compounds of formula (IV) from compounds of formula (Ib) include those described in Schemes 5, 6, 8 and 9 for the preparation of compounds of formula (Ilia). Methods useful for converting compounds of formula (Ilia) to compounds of formula (IV) are described in great detail in WO/2005/118565, incorporated herein by reference in its entirety.

After diastereomeric purification by recrystallization, the compound of formula (Ib) can be reacted under appropriate conditions to obtain the compound of formula (IV). Alternatively, the suitable conditions may include dissolving the crystalline compound of formula (Ib) in a solvent prior to reacting it under suitable conditions to form the compound of formula (IV).

In additional embodiments, the yield of the compound of formula (IV) from the compound of formula (Ib) is greater than about 50%, greater than about 60%, or greater than about 70%.

In other embodiments, the present invention also relates to formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III ), (IIIa), (IV), (V) or other compounds described herein. The present invention also relates to substantially diastereoisomer-free compositions comprising compounds of any of these formulae. The present invention also relates to each of the intermediates and processes described herein.

In additional embodiments, the present invention is directed to compositions comprising substantially diastereomer-free compounds described herein, such as compounds having the opposite stereochemistry at the chiral carbons marked with an asterisk in Scheme 1 . The present invention also relates to methods for synthesizing the compound of formula (IV), B-1939 or other halichondrin B analogs by using these compounds.

This invention relates at least in part to processes and intermediates for the conversion of compounds of formula (I) to compounds of formula (III). The compound of formula (III) can also be converted into compound (IV) and/or halichondrin B or its analogues.

Compounds of formula (III) can be synthesized by methods described herein. The present invention relates at least in part to all compounds and intermediates described herein and methods of synthesizing said compounds and intermediates.

Compound 2-1 is converted into the compound of formula (Ib)

As shown in Scheme 2, compounds of formula (Ib) can be synthesized from compounds of formula 2-1:

Scenario 2

Compound 2-1 can be converted into compound (Ib). In Scheme 2, L ^1a and L ^1b are protecting groups. Examples of protecting groups include, but are not limited to, C ₁ -C ₆ alkyl ethers, aryl (C ₁ -C ₆ ) alkyl ethers, silyl (C ₁ -C ₁₀ ) ethers, C ₁ -C ₆ alkyl Esters, cyclic C ₁ -C ₆ acetals, cyclic C ₂ -C ₇ ketals and cyclic carbonates. Examples of R ² include hydrogen, C ₁ -C ₆ alkyl (such as methyl, tert-butyl, etc.), C ₄ -C ₁₀ aryl (such as phenyl) and C ₄ -C ₁₀ aryl-C ₁ -C ₆ Alkyl (such as benzyl). Examples of R ³ and R ⁴ include CH ₃ and OCH ₃ , respectively, or R ³ and R ⁴ may be (—CH ₂ CH ₂ ) ₂ O together.

Compound 2-1 can be converted into compound 2-4 by using an appropriate reducing agent. Examples of such reducing agents include, but are not limited to, alanates and borohydrides (eg, BH ₃ , AlH ₃ , LiBH ₄ , LiAlH ₄ , NaBH ₄ , NaAlH ₄ , ZnBH ₄ ).

The hydroxyl group in compound 2-4 can be converted to a leaving group such as but not limited to a sulfonate (such as MsO-, TsO-, TfO-) or a halide by methods described in the literature. This is then reacted with a cyanide source such as KCN or NaCN to generate compounds 2-5.

Alternatively, compounds 2-4 can be converted to compounds 2-5 by oxidation of hydroxyl groups to aldehydes by methods described in the literature. Aldehydes can be converted to nitriles with suitable reagents such as, but not limited to, dimethyl cyanophosphonate/samarium iodide. Compounds 2-5 can be alkylated in a suitable solvent such as an aprotic solvent such as THF, toluene, TBME, and then reacted with a strong base such as a metal amide or a metal alkoxide (such as LDA, KHMDS or KO ^t Bu) and a suitable Alkyl halides (such as X-Me) or sulfonate esters react to form compounds of formula (Ib).

Alternatively, compound 2-1 can be converted to compound 2-7 by methods known in the art. Examples of such methods include, but are not limited to, treatment with N,O-dimethylhydroxylamine hydrochloride/trimethylaluminum. Compounds 2-7 can be converted to compounds of formula (Id) by treatment with an appropriate carbon-nucleophile. Examples of such nucleophiles include, but are not limited to, alkyl Grignard reagents.

Alternatively, oxidation of compounds 2-4 to aldehydes followed by addition of alkyl Grignard reagents or other carbon-nucleophiles affords secondary alcohols. Oxidation using known methods affords compounds of formula (Id). Compounds of formula (Ib) can be synthesized, for example, by treating compounds of formula (Id) with TosMIC in the presence of metal alkoxides such as NaOEt and KotBu (J.Org.Chem.42(19), 3114-3118, (1977)) . Alternatively, compounds of formula (Id) can be converted to compounds of formula (Ib) using reagents such as, but not limited to, dimethyl cyanophosphonate/samarium iodide.

(-)-quinic acid is converted into a compound of formula (Id)

Alternatively compounds of formula (Id) can be synthesized as shown in Scheme 3.

Option 3

In Scheme 3, L ^1a and L ^1b are protecting groups, as shown in Scheme 2. L ^2b and L ^2c are also protecting groups such as but not limited to cyclic acetals (X=O and/or S), cyclic ketals (X=O and/or S) and cyclic carbonates (X=O ).

The synthesis of compounds 3-9 from commercially available (-)-quinic acid has been described previously (WO/2005/118565). Compounds 3-9 can be reduced to lactols 3-10 with DIBAL or other reagents known in the art such as alanates and borohydrides. Lactol 3-10 can be converted to compound 3-11 using Wittig or Julia olefination. Deprotection followed by double bond migration and Michael addition affords compound (Id).

More specifically, MeC(OL ^2b )(OL ^2c )CH ₂ CH ₂ PPh ₃ (prepared in situ) can be employed in a polar solvent such as THF, MeOH or DMF at temperatures ranging from 0°C to 50°C A Wittig olefination was performed. Acid-catalyzed sequential reactions such as deprotection, migration and Michael addition can be performed with an acid such as TsOH or HCl in a polar solvent such as THF or acetone at a temperature range of 10-30°C for about 2-4 hours. Alternatively, migration and Michael addition can also be performed with a base such as NaOMe in a polar solvent such as THF or MeOH.

Compound 4-1 is converted into a compound of formula (I)

As shown in Scheme 4, the compound of formula 4-1 (diastereomeric mixture) can be obtained by isomerization and crystallization to the compound of formula (I).

Option 4

In Scheme 4, z is a single bond or a double bond, provided that when z is a ^double bond, X2 is C and ^Y1 is hydrogen; provided that when z is ^a single bond, X2 is ^CH or O; X1 is O, S or CN, provided that when X ¹ is CN or S, X ² is O; Y ¹ is a halide, hydrogen, or OL ² , or when X ² is O, Y ¹ is absent; L ¹ and L ² is independently selected from ^hydrogen and ^a protecting group, or L and L together are ^a protecting group, with the proviso that when X is CN, L is ^absent .

Diastereoisomers of formula 4-1 can be converted to compounds of formula (I) by treatment with a substoichiometric amount of an amide base such as KHMDS at low temperature (such as below about -30°C) . Once quenched, the compound of formula (I) can be isolated and recrystallized from a suitable crystallization solvent system such as, but not limited to, heptane/tert-butyl methyl ether and heptane/isopropanol.

Alternatively, crystallization-induced dynamic resolution (CIDR) can also be used to selectively crystallize compounds of formula (I). For example, diastereoisomers of formula 4-1 may be treated with a base such as an alkoxide (eg tert-butoxide or isopropoxide) in a suitable crystallization solvent system. Examples of suitable solvent systems for crystallization include combinations of protic solvents such as isopropanol and antisolvents such as heptane that yield purified compounds of formula (I) at non-low temperatures.

The compound of formula (Ib) is converted into compound 5-13

Option 5

In Scheme 5, L ^1a and L ^{1b are} as described above in Scheme 2. L ^1d is a suitable protecting group, such as C ₁ -C ₆ alkyl ether, aryl (C ₁ -C ₆ ) alkyl ether, C ₁ -C ₆ ester or silyl (C ₁ -C ₁₀ ) ether .

Depending on the nature of L ^1a and L ^1b , compounds of formula (Ib) can be deprotected by various methods known in the art. Examples of deprotection reactions include, but are not limited to, hydrogenation, reduction, oxidation, base-induced deprotection, and acid-induced deprotection. A person of ordinary skill in the art should be able to select an appropriate technique according to techniques recognized in the art (see, eg, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, Inc).

Once L ^1a and L ^1b are removed, the deprotected compound 5 can be deprotected by treating compound 5-12 with 2-acetoxy-2-methylpropionyl bromide, a catalytic amount of water in a polar aprotic solvent such as acetonitrile -12 was transformed into compound 5-13. The resulting intermediate can be treated with a base such as diazabicycloundecane (DBU) to afford compounds 5-13.

Alternatively, compound 5-12 can be converted to compound 5-13 using a multi-step process. The method involves selectively activating one hydroxyl group as a halide, MsO-, TsO- or TfO- and protecting the remaining hydroxyl group. Suitable protecting groups for this step include L ^1d groups such as C ₁ -C ₆ alkyl ethers, aryl (C ₁ -C ₆ ) alkyl ethers, C ₁ -C ₆ esters and silyl (C ₁ - C ₁₀ ) ethers. This intermediate can be converted to compound 5-13 using methods described previously.

Compound 5-13 is transformed into compound 6-16

Option 6

In Scheme 6, L ^1d is hydrogen or a protecting group, C ₁ -C ₆ alkyl ether, aryl (C ₁ -C ₆ ) alkyl ether, C ₁ -C ₆ ester or silyl (C ₁ - C ₁₀ ) ether). L ^1c can be hydrogen or a protecting group such as but not limited to glycoside, C ₁ -C ₆ alkyl or C ₁ -C ₆ ester. ^X2 and ^X3 can each be oxygen or hydroxyl.

Oxidative cleavage of olefinic compounds 5-13 can be carried out with ozone in a suitable solvent such as methanol at a temperature below 0°C. Ozone adducts can be treated using literature methods to afford ^compounds 6-14, where X2 and ^X3 are each carbonyl or hydroxyl. Alternatively, metal oxides such as osmium tetroxide or potassium permanganate and sodium periodate can also be used to obtain ^compounds 6-14, wherein each of X2 and ^X3 is a carbonyl group.

When each of X2 and ^X3 is a carbonyl group, they can be reduced to give ^compound 6-14, wherein each of ^X2 and ^X3 is a hydroxyl group. Deprotection ^of L1 can be accomplished using literature methods such as potassium carbonate in methanol to give compounds 6-15. Compound 6-15 can be treated with _NaIO4 to afford compound 6-16, wherein L ^1c is H. Alternatively, compound 6-16 may contain a glycoside (eg L ^1c is C ₁ -C ₃ alkyl such as methyl) protecting group, which can be added by methods known in the art such as methanol in the presence of an acid catalyst.

Compound 2-1 is transformed into compound 6-16

Option 7

In Scheme 7, an alternative route for the preparation of compounds 6-16 is shown. Examples of R ² include hydrogen, C ₁ -C ₆ alkyl (such as methyl, tert-butyl, etc.), C ₄ -C ₁₀ aryl (such as phenyl) and C ₄ -C ₁₀ aryl-C ₁ -C ₆ Alkyl (such as benzyl). L ^1a and L ^1b are protecting groups as described above. Examples of L ^1c include hydrogen and protecting groups such as glycoside, C ₁ -C ₆ alkyl and C ₁ -C ₆ acetyl.

Compound 2-1 can be converted to compound 7-17d as depicted in Schemes 5 and 6. Compound 7-17d was treated with TosMIC and isomerized/crystallized to give compound 6-16, as shown in Schemes 2 and 4.

Compound 5-16 is transformed into compound 7-20

Option 8

Compounds 8-20 can be prepared from 6-16 as shown in Scheme 8. In Scheme 8, L ^1c is hydrogen or a protecting group as described above; L ⁵ is C ₁ -C ₁₀ alkyl, C ₄ -C ₁₀ aryl-C ₁ -C ₆ alkyl or C ₄ -C ₁₀ aryl; Y ² is sulfonate or halide.

When L ^1c is other than hydrogen, the ethers are hydrolyzed using literature methods to give lactols (6-16, L ^1c = H). This lactol (6-16, L1c=H) is converted to compounds 8-18 by olefination reactions such as the stable Wittig reaction, Wadsworth-Horner-Emmons reaction or Julia olefination reaction. The Wittig olefination reaction can be carried out with a stable ylide such as Ph ₃ PCHCO ₂ L ⁵ in a polar solvent such as THF, MeOH or DMF at an appropriate temperature (such as -78°C-50°C). The Wadsworth-Horner-Emmons olefination reaction can use a stable ylide (such as (MeO) ₂ POCH ₂ CO ₂ L ⁵ ) in a polar aprotic solvent (such as THF or ACN) at an appropriate temperature (such as -78°C- 25° C.) in the presence of a suitable base such as tBuOK, NaH or LiCl/tertiary amines (such as DBU ^{, iPr2Net} , _{Et3N )} .

Variations on these conditions are known in the art. See, for example, Org. React. 25, 73-253, (1977) and Tetrahedron Lett. 25, 2183 (1984) for variations on the Wadsworth-Horner-Emmons olefination. In addition, the Julia olefination reaction can be performed in polar aprotic solvents such as THF, DME or halogenated solvents such as CH ₂ Cl ₂ in alkylsulfonates such as alkyl(benzothiazol-2-ylsulfonyl) acetate) and a suitable base (such as BuLi, LDA, KHMDS or DBU) at an appropriate temperature (such as -78°C-25°C). Variations of these conditions for the Julia olefination reaction are apparent from the literature (see, Org. Biomol. Chem. 3, 1365-1368, (2005); Synlett, 26-28, (1998)).

Compounds 8-19 can be obtained from 8-18 by catalytic hydrogenation in polar solvents such as EtOAc, MeOH in the presence of metal catalysts such as palladium (Pd/C) or platinum (PtO ₂ ) conduct. Preferably, the reaction is carried out under hydrogen at a pressure ranging from 0.04 bar to 1.10 bar.

Using a suitable sulfonylanhydride or sulfonyl chloride (such as MsCl, TsCl or Tf ₂ O) in a polar aprotic solvent (such as THF or a halogenated solvent (such as CH ₂ Cl ₂ )) in a suitable base (such as Et In the presence of ₃ N), the hydroxyl group of 8-19 can be converted into a leaving group (such as MsO-, TsO-, TfO-) to obtain 8-20.

Optionally, the 8-20 leaving group can be converted to a halide. The reaction can be performed in a polar solvent such as DMF or acetone in the presence of a halogenated reagent such as NaI or NaBr. Alternatively, the conversion of the hydroxy group to a halide can be performed using a halogenating reagent such as NIS or NBS in a polar solvent such as THF in the presence _of Ph3P and a suitable base such as pyridine.

Compound 6-15 is transformed into compound 8-20

Option 9

In Scheme 9, another method for the conversion of compounds 6-15 to compounds 8-20 is shown. In scheme 9, R ^9a and R ^9b are hydrogen, C ₁ -C ₆ alkyl or together are carbonyl; Y ² is sulfonate or halide; Y ³ is O, OL ³ or CHCO ₂ -L ₃ , wherein L ³ is hydrogen or a protecting group.

As shown in Scheme 9, compound 8-20 can be prepared from compound 6-15 by using the method of protecting 1,2 diol in the literature. Treatment of the neopentyl-hydroxyl of compound 9-21 (using the method described in Scheme 8) affords 9-22. Compound 9-22 was deprotected using literature methods to afford the diol. Treatment of this diol with a reagent such as sodium periodate affords aldehyde 9-23 ( ^Y3 =O). Aldehydes 9-23 were treated as described in Scheme 8 to afford compounds 8-20.

Compound 7-17b is transformed into 8-20

Scheme 10

Alternatively, compounds 7-17b can be converted to compounds 8-20 as shown in Scheme 10. In scheme 10, R ² includes C ₁ -C ₆ alkyl such as methyl, ethyl and tert-butyl; R ^10a and R ^10b are hydrogen, C ₁ -C ₆ alkyl or together are carbonyl; Y ² is sulfo Ester or halide; Y ³ is O, OL ³ or CHCO ₂ -L ₃ . L ³ is hydrogen or a protecting group.

Compounds 7-17b can be converted to compounds 10-17f by selective protection of the 1,2-diol followed by conversion of the functional group neopentyl hydroxy to a sulfonate or halide. Selective protection of 1,2-diols can be carried out with aldehydes, ketones, acetals or carboxylchlorides (such as DMP, cyclohexanone, _MeOPhCHO or Ph3P) in the presence of acid catalysts. Functional group conversion of neopentyl hydroxyl to sulfonate or halide has been described previously in Scheme 8. Compounds 10-17g and 10-22 can be prepared in a similar manner as described in Scheme 2 above. Deprotection of the diol protecting group using literature methods followed by treatment with sodium periodate affords 10-23 (Y=O). A Wittig, Horner-Wadsworth-Emmons or Peterson type olefination followed by hydrogenation affords compounds 8-20.

D. Chemical Example

Example 1: Synthesis of Compound AD from Compound AC

Scheme 11

Compound AC (1Wt, 1V, 1eq) was dissolved in THF (1.80V) and cooled to -75°C. KHMDS (0.50 M in toluene, 6.60 V, 1.10 eq) was added at such a rate that the internal temperature did not exceed -65 °C. After the addition was complete, stirring was continued at -75°C for 30 minutes. A solution of MeI (0.188 V, 1.01 eq) in THF (0.50 V) was added at such a rate that the internal temperature did not exceed -65 °C. After the addition was complete, stirring was continued at -75°C for 1 hour. KHMDS (0.50M in toluene, 0.60V, 0.10eq) was added at such a rate that the internal temperature did not exceed -70°C, and stirring was continued at -75°C for 2.5 hours. Under vigorous stirring, 20wt% _NH4Claq (1.50Wt, 1.9eq) was added at such a rate that the internal temperature did not exceed -55°C. After the addition was complete, the resulting mixture was warmed to -20°C. Water (1.50V) was added and the mixture was rewarmed to 0°C. The biphasic mixture was transferred to a workup vessel (the reactor was washed with MTBE (0.40V)) and vigorous stirring was continued for 2 minutes. The aqueous layer was set aside and the organic layer was washed with water (2.0V). The organic layer was concentrated and residual solvent and water were removed azeotropically with heptane (1.50Vx2) to give the crude product as a yellow solid (1.1Wt, dr=4.4:1).

The crude product (1.1 Wt) was suspended in heptane-MTBE (4:1 v/v, 5.0 V) and heated to 80 °C. The resulting solution: 1) cooled to 70°C for 1 hour; 2) kept at 70°C for 0.5 hours; 3) cooled to 65°C for 0.5 hours (precipitation); 4) kept at 65°C for 0.5 hours; 5) kept at 0.5°C 6) Keep at 50°C for 0.5 hours; 7) Cool to room temperature and continue to stir for 40 hours. The crystals were collected by filtration, washed with heptane (1Vx2), dried under _N2 /vacuum to give compound AD as a beige powder (0.69Wt, 0.66eq, dr=34:1). The mother liquor was concentrated to give the epimer (Compound AS) as a yellow solid (Epimer, 0.38 Wt, dr Compound AD:Epimer = 1 :2.2).

Example 2: Diastereomeric purification of compound AS to compound AD

Scheme 12

Using stereoselective deprotonation-protonation or crystallization-induced dynamic resolution (CIDR), each of the following methods was used to convert the undesired C25 epimer in the reaction shown in Scheme 12 to the desired C25 isomer.

Method 1: Compound AS (1Wt, 1V, dr=1:2.2) was dissolved in toluene (2.6V) and cooled to -20°C. KHMDS (0.50M in toluene, 3.4V, 0.60eq) was added at such a rate that the internal temperature did not exceed -16°C. After the addition was complete, stirring was continued at -20°C for 15 minutes. Under vigorous stirring, 20 wt% _NH4Claq (1.0 Wt, 1.3 eq) was added at such a rate that the internal temperature did not exceed -15 °C. After 5 minutes, the mixture was warmed to 0 °C. The organic layer was separated, washed with water (2.0V), and concentrated. Residual solvent and water were removed azeotropically with heptane (3.0Vx2) to give the crude product as a yellow solid oil mixture (dr = 2.6:1). The crude product was suspended in heptane-MTBE (5:1, v/v, 3.0 V) and heated to 80 °C. The resulting clear solution was cooled to room temperature (23°C) over 3 hours (precipitation started at 45°C). The crystals were collected by filtration, washed with: 1) heptane-MTBE (5:1 v/v, 1.0 V); 2) heptane (1.0 V), and dried under _N2 /vacuum to give compound AD as a white powder (0.31Wt, 0.31eq, 0.08eq). The mother liquor was concentrated to obtain compound AS (0.69Wt, dr=1:1).

Method 2: Compound AS (1Wt, 1V, dr=1:1) was dissolved in heptane-MTBE (5:1v/v, 2.0V), and KHMDS (0.50M in toluene, 0.40V, 0.07eq). Stirring was continued for 10 minutes and the mixture was cooled to 0°C. Compound AD (0.0001 Wt, 0.0001 eq) was added and stirring was continued for another 30 minutes (precipitation increased). 20 wt% _NH4Claq (0.20Wt, 0.26eq) was added under vigorous stirring. The resulting mixture was diluted with EtOAc (2.0 V) to dissolve compound AD precipitate. The organic layer was separated, washed with water (1.0 V), and concentrated. The residual solvent and water were removed azeotropically with heptane (5Vx2) to give the crude product as a yellow solid oil mixture (dr = 2.3:1). The crude product was suspended in heptane-MTBE (3:1 v/v, 1.5 V) and heated to 80 °C. The resulting clear solution was cooled to 20°C over 3 hours (precipitation started at 50°C). The crystals were collected by filtration, washed with heptane-MTBE (4:1 v/v, 1V), dried under _N2 /vacuum to give compound AD as a white powder (0.22Wt, 0.22eq, 0.04eq).

Method 3 (CIDR): Compound AS (1Wt, 1V, dr=1:5) was dissolved in heptane (5V) at 23°C. t-BuOK (1.0 M in THF, 0.29 V, 0.10 eq) was added and stirring was continued for 10 minutes. The precipitate was collected by filtration, washed with heptane (10V), and dried to give compound AD as a beige powder (0.36Wt, 0.36eq, dr=7.3:1, filtrate dr=3.7:1). Method 4: Compound AS (1Wt, 1V, 1eq, dr=1:1.7) was dissolved in toluene (5.0V) and cooled to -70~-75°C. KHMDS (0.5M in toluene, 0.500eq, 2.88V, 2.53Wts) was added while maintaining the internal temperature below -65°C. The resulting mixture was then cooled to -70~-75°C, and stirred at -70~-75°C for 4 hours. 20 wt% _NH4Cl (aq, 2.00 Wts) was added while maintaining the internal temperature below -60°C. After the addition was complete, the mixture was warmed to 0°C over 1.5-2 hours. MTBE (4.00V, 2.96Wt) and water (4.00V, 4.00Wt) were added with stirring and the resulting biphasic mixture was partitioned. The organic layer (dr=6.5:1) was separated and washed sequentially with: 1) 20 wt% citric acid (aq, 1.0Wt); 2) water (3.00V); 3) water (3.00V), partially under vacuum Concentrated to ~2V. The residue was solvent exchanged with heptane (6.00Vx2, partially concentrated in vacuo to ~2V each time) and diluted with heptane-IPA (6:1 v/v, 3.5V). The mixture was heated to 60°C, cooled to 15-20°C over 4 hours, and stirred overnight at 15-20°C. The crystals were collected by filtration, rinsed with heptane-IPA (9:1 v/v, 2.0V), dried under N2/vacuum to give compound AD (0.4Wt, 0.4eq, dr=57:1) as light brown powder.

¹ HNMR (500MHz, CDCl ₃ )

δ4.40-4.44(1H, m), 4.30(1H, dd, J=6.5, 3.5Hz), 4.09(1H, dd, J=6.5, 3.0Hz), 3.72-3.77(1H, m); 3.37( 1H, dd, J=10.0, 6.5Hz), 2.91-2.99 (1H, m), 2.35-2.39 (1H, m), 2.07-2.12 (1H, m), 1.97-2.03 (1H, m), 1.96 ( 1H, dd, J = 14.0, 4.0Hz), 1.82 (1H, d, J = 12.0Hz), 1.58-1.70 (5H, m), 1.50-1.58 (6H, m), 1.42-1.49 (1H, m) , 1.32-1.40 (2H, m), 1.29 (3H, d, J=7.0Hz), 1.11-1.20 (1H, m)

¹³ CNMR (125MHz, CDCl ₃ )

δ122.95, 110.58, 78.29, 76.28, 75.92, 75.81, 72.16, 68.34, 43.80, 40.51, 37.61, 34.52, 29.85, 28.92, 27.24, 25.33, 24.24, 23.84, 22.50, 18.55

LRMS(ESI)m/z measured value 370.15[M+Na] ⁺

Melting point 123°C

Example 3: Synthesis of Compound AJ from Compound AD

Scheme 13

Compound AD (1Wt, 1V) was suspended in AcOH (5.00V, 31eq) at 20°C. 1.00M HClaq (2.48V, 1.00eq) was added and stirring was continued at 20°C for 5 hours. The reaction mixture was cooled to 0°C and 50 wt% NaOHaq (2Wt, 8eq) was added while keeping the internal temperature below 10°C. Heptane-MTBE (2:1 v/v, 10.0 V) was added and vigorous stirring was continued for 3 minutes. The organic layer was set aside and the aqueous layer was extracted with acetonitrile (10.0Vx2). All acetonitrile layers were combined, washed with brine (2.0 V), and concentrated. The residual solvent was removed azeotropically with acetonitrile (8.0Vx2) to give the crude product as a yellow solid (0.62Wt, 0.080eq).

Crude compound AJ (1Wt, 1V) was suspended in IPA (6.0V) and heated to 80°C. The resulting solution was cooled to room temperature over 1 hour. The mixture was recooled to 0°C and stirring was continued at 0°C for a further 1 hour. The precipitate was collected by filtration, washed with cold IPA (2.0V) and dried to give compound AJ as a white powder (0.72Wt, 0.72eq).

¹ HNMR (500MHz, CDCl ₃ )

δ4.37 (1H, dd, J = 6.5, 5.0Hz), 3.97-4.04 (1H, m), 3.88-3.89 (1H, m), 3.74-3.79 (1H, m), 3.42 (1H, dd, J =10.0, 7.0Hz), 2.91-2.99(1H, m), 2.56(1H, br), 2.37-2.41(1H, m), 2.27(1H, br), 2.05-2.11(1H, m), 1.96- 2.00(1H, m), 1.82(1H, d, J=11.5Hz), 1.75(1H, t, J=11.5Hz), 1.65-1.70(1H, m), 1.54-1.61(2H, m), 1.47 -1.53(1H, m), 1.32(3H, d, J=7.0Hz), 1.15-1.24(1H, m)

¹³ CNMR (125MHz, CDCl ₃ )

δ122.93, 77.71, 77.00 (overlapped with chloroform signal), 73.60, 69.14, 68.45, 67.04, 43.66, 40.38, 29.88, 28.85, 28.37, 22.48, 18.53

¹³ CNMR (125MHz, acetone-d6)

δ122.60, 77.77, 77.04, 73.32, 69.40, 68.34, 66.55, 44.02, 40.11, 29.93, 28.74, 28.16, 22.25, 17.95

LRMS(ESI)m/z measured value 289.95[M+Na] ⁺

Melting point 189°C

Example 4: Synthesis of Compound AK from Compound AJ

Scheme 14

Compound AJ (1Wt, 1V, 1eq) was suspended in acetonitrile (5.00V) and cooled to 0°C. 2-Acetoxy-2-methylpropionyl bromide (0.938 Wt, 0.656 V) was added at such a rate that the internal temperature did not exceed 7°C. After the addition was complete, water (0.002V, 3mol%) was added and stirring was continued at 0°C for another 1 hour. The reaction mixture was diluted with MTBE (5.0V). After the internal temperature had dropped to 0°C, 10 wt% _NaHCO3aq (5.0V, 3.4eq) was carefully added under vigorous stirring, keeping the internal temperature below 7°C, and the resulting mixture was partitioned. The organic layer was set aside and the aqueous layer was extracted with MTBE (5.0V). All organic layers were combined and washed sequentially with: 1) 10 wt% NaHCO ₃ aq (2.0 V, 1.4 eq); 2) water (2.0 V); 3) brine (2.0 V) and concentrated to give crude compound AK as Light brown oil (1.47Wt, 1.04eq). The crude product was azeotropically dried with toluene (4Vx3) and used in the next reaction without purification.

¹ HNMR (500MHz, CDCl ₃ )

δ5.20 (1H, br), 4.38 (1H, dd, J=6.5, 3.5Hz), 4.21-4.23 (1H, m), 4.04 (1H, dd, J=10.0, 7.0Hz), 3.79-3.83 ( 1H, m), 2.90-2.98 (1H, m), 2.51-2.56 (2H, m), 2.30-2.34 (1H, m), 2.11-2.15 (1H, m), 2.07 (3H, s), 1.65- 1.71(1H, m), 1.57-1.62(3H, m), 1.49-1.55(1H, m), 1.32(3H, d, J=6.5Hz), 1.21-1.30(1H, m)

¹³ CNMR (125MHz, CDCl ₃ )

δ169.39, 122.79, 78.13, 75.49, 75.42, 73.76, 68.45, 44.66, 43.48, 40.11, 29.48, 28.88, 28.38, 22.40, 21.12, 18.46

LRMS(ESI) m/z measured value 393.96[M+Na] ⁺

Example 5: Synthesis of Compound AL from Compound AJ

Scheme 15

Compound AJ (1Wt, 1V, 1eq) was suspended in acetonitrile (3.0V) and cooled to 0°C. 2-Acetoxy-2-methylpropionyl bromide (1.02 Wt, 1.30 eq) was added at such a rate that the internal temperature did not exceed 2°C. After the addition was complete, an acetonitrile-water mixture (water (0.0020V, 0.030eq) and acetonitrile (0.020V)) was added and stirring was continued at 0°C for 2 hours. With vigorous stirring, 10 wt% NaHCO3aq (5.0V) was added at such a rate that the internal temperature did not exceed 8°C ( _CO2 evolution). Toluene (4.3Wt, 5.0V) was added and vigorous stirring was continued for 3 minutes. The mixture was partitioned and the organic layer was set aside. The aqueous layer was extracted with toluene (2.6Wt, 3.0V). All organic layers were combined and washed sequentially with: 1) 10 wt% _NaHCO3aq (3.0V); 2) water (2.0V).

The organic layer was transferred to a reactor, and 5 Wt of solvent was distilled off under atmospheric pressure. The distillation involved heating the organic layer to 90°C to remove acetonitrile, then heating the mixture to about 110°C to remove toluene. After cooling to 80°C, toluene (2.50Wt, 3V) was added followed by DBU (1.12V, 1.14Wt, 2.00eq). The mixture was reheated to 100°C and stirred vigorously for 17 hours. The reaction mixture was cooled to 0°C and 1.00 MHClaq (4.5V, 1.2eq) was added at such a rate that the internal temperature did not exceed 8°C. The resulting mixture was partitioned. The organic layer was set aside and the aqueous layer was extracted with toluene (1.73Wt, 2.0V). All organic layers were combined, washed sequentially with: 1) 1.00MHClaq (0.50V, 0.13eq); 2) 10wt% NaHCO3aq (1.0V); ₃ ) water (2.0Wt, 2.0V), and concentrated. Residual toluene was removed azeotropically with IPA (2.0 V) to give the crude product as a yellow solid. Crude compound AL was suspended in IPA (5.0 V) and heated to 80 °C. The resulting solution was cooled to 0°C over 2 hours and stirring was continued at 0°C for an additional 30 minutes. The crystals were collected by filtration, washed with cold IPA (1V), then heptane (1V), and dried to give compound AL as a white powder (0.64Wt, 0.59eq). The mother liquor was concentrated and diluted with IPA-heptane (1:1 v/v, 1.0V). A white precipitate formed which was collected by filtration and washed with: 1) IPA-heptane (1:1 v/v, 0.4V); 2) heptane (0.4V) and dried to give additional compound AL (0.043Wt, 0.040 eq).

Example 6: Synthesis of Compound AL from Compound AK

Scheme 16

Compound AK (1Wt, 1V, 1eq) was dissolved in toluene (5.0V). DBU (0.818Wt, 0.803V, 2.0eq) was added at 23°C and the resulting mixture was heated to 100°C. When compound AK was consumed completely, the reaction mixture was cooled to 10°C, and 1M HCl (3.5V, 1.3eq) was added. The resulting mixture was stirred vigorously for 5 minutes and allowed to partition. The organic layer was set aside and the aqueous layer was extracted with MTBE (5.0V). All organic layers were combined, washed sequentially with: 1) water (2.0V); 2) 10 wt% _NaHCO3 solution (2.0V); 3) water (2.0V), and concentrated to give a mixture of light brown oil and water . Residual water was removed azeotropically with heptane (3.0Vx3) to afford crude compound AL as a yellow solid (0.65Wt, 0.83eq).

¹ HNMR (500MHz, CDCl ₃ )

δ6.16(1H, d, J=10Hz), 5.60-5.63(1H, m), 5.01-5.02(1H, m), 4.34-4.36(1H, m), 3.80-3.85(1H, m), 3.42 (1H, dd, J=5.0, 2.0Hz), 2.93-3.01 (1H, m), 2.53-2.57 (1H, m), 2.07-2.12 (1H, m), 2.03 (3H, s), 1.56-1.72 ( 4H, m), 1.49-1.55 (1H, m), 1.32 (3H, d, J=6.5Hz), 1.22-1.30 (1H, m)

¹³ CNMR (125MHz, CDCl ₃ )

δ170.10, 142.16, 122.82, 122.42, 79.43, 75.26, 74.81, 69.52, 68.48, 40.36, 29.62, 28.90, 28.77, 22.49, 21.26, 18.54

LRMS(ESI) m/z measured value 314.04[M+Na] ⁺

Melting point 92°C

Example 7: Synthesis of Compound AM from Compound AL

Scheme 17

Compound AL (1Wt, 1V, 1eq) was dissolved in MeOH-DCM (5:3v/v, 8.0V) and cooled to -47°C. _O3 was bubbled through the mixture keeping the internal temperature below -42°C. After compound AL was consumed, excess O ₃ was removed by passing through N ₂ until the peroxide at the outlet of the reactor was determined to be negative.

The reaction mixture was then warmed to -25°C and NaBH4 ( _0.0753Wt , 0.580eq) was added while maintaining the internal temperature below -17°C. After the addition was complete, the mixture was stirred at -20°C for 1 hour and then warmed to 0°C. NaBH4 (pellets, _0.0753Wt , 0.580eq) was added (while keeping the internal temperature below 3°C) and stirring was continued at 0°C for 1 hour.

K2CO3 ( _0.712Wt , _1.50eq ) was added at 0°C and the reaction was warmed to 20°C. After the acetate intermediate was completely consumed (about 4 hours), the reaction mixture was cooled to 0°C, and wt% HClaq (5.1Wt, 4.1eq) was added under vigorous stirring to adjust the pH to 6-7.

The resulting biphasic mixture was partially concentrated (to about 5.6 Wt) to remove volatiles, diluted with water-THF (1:1 v/v, 4.0 V), and cooled to 15°C. _NaIO4 (1.47Wt, 2.00eq) was added and the resulting slurry was stirred at 20°C until complete consumption of the triol (about 3 hours). The reaction mixture was then diluted with EtOAc (6.0 V), stirred vigorously for 5 min, and filtered through a pad of celite (2 Wt). The filtrate (F-1) was separated and set aside, the filter cake was washed with EtOAc-EtOH (9:1 v/v, 4.0 V) (filtrate: F-2). NaCl (1.0 Wt) was added to F-1 and the resulting mixture was stirred vigorously for 5 minutes and allowed to partition. The organic layer was set aside, and the aqueous layer was extracted with F-2. All organic layers were combined and washed successively with: ₁ ) 10wt% Na2S2O3aq (1.0Wt); ₂ ) water (1.0V); ₃ ) water (1.0V). Concentration afforded a white solid. Residual water and solvent were azeotroped with EtOAc (6.0Vx3) to give the crude product as a white solid (0.84Wt, 0.96eq). The crude product was suspended in Heptane-EtOAc (1:1 v/v, 3.5V) and heated to 80 °C. The resulting solution was cooled to room temperature over 2 hours (precipitation started at -65°C). The mixture was recooled to 0°C and stirring was continued for 1 hour. The crystals were collected by filtration, washed with cold heptane-EtOAc (1:1 v/v, 1.8V), dried under _N2 /vacuum to afford compound AM as a white powder (0.58Wt, 0.67eq). The mother liquor was concentrated, suspended in heptane-EtOAc (4:3 v/v, 0.9 V) and heated to 80 °C. The resulting clear solution was cooled to 20°C over 2 hours. The mixture was recooled to 0°C and stirring was continued for 1 hour. The crystals were collected by filtration, washed with cold heptane-EtOAc (4:3 v/v, 0.50V), dried under _N2 /vacuum to afford additional compound AM as a white powder (0.068Wt, 0.08eq).

¹ HNMR (major anomer, 500 MHz, CDCl ₃ )

δ4.96(1H, s), 4.17(1H, dd, J=6.0, 3.5Hz), 3.90(1h, d, J=9.5Hz), 3.82-3.74(2H, m), 3.41(1H, dd, J=10, 3.0Hz), 3.01(1H, s), 2.95-2.85(1H, m), 2.51-2.45(1H, m), 2.22-2.15(1H, m), 1.72-1.64(1H, m) , 1.63-1.48 (3H, m), 1.29 (3H, d, J=13Hz), 1.30-1.18 (1H, m)

¹³ CNMR (main anomer, 125MHz, CDCl ₃ )

δ122.81, 92.46, 77.17, 75.70, 72.43, 71.18, 68.36, 40.28, 29.82, 28.70, 28.40, 22.42, 18.52

LRMS(ESI)m/z measured value 307.99[M+MeOH+Na] ⁺

Melting point 116°C

Example 8: Synthesis of Compound AN from Compound AM

Program 18

Compound AM (1Wt, 1V, 1eq) was suspended in acetonitrile (4.0V) and cooled to 10°C. LiCl (0.184Wt, 1.10eq) was added followed by N,N-diisopropylethylamine (0.825V, 1.20eq). After the internal temperature dropped to 10°C, trimethylphosphonoacetate (0.703V, 1.10eq) was added at such a rate that the internal temperature did not exceed 13°C. After the addition was complete, the reaction was stirred at 10°C for 1 hour, then warmed to 20°C. Stirring was continued at 20 °C until compound AM was completely consumed. The reaction mixture was diluted with MTBE (8.0 V) and cooled to 0°C. 1.00M HClaq (5.0V, 1.5eq) was added with vigorous stirring while maintaining the internal temperature below 8°C and the resulting biphasic mixture was partitioned. The organic layer was set aside and the aqueous layer was extracted with MTBE (4.0V & 2.0V). All organic layers were combined and washed sequentially with: 1) 10 wt% NaHCO ₃ aq (3.0 V); 2) water (2.0 V) and concentrated to give compound AN as a light yellow oil (E:Z ~ 20:1 ).

¹ HNMR (500MHz, CDCl ₃ )

δ6.87 (1H, dd, J = 16.0, 3.5Hz), 6.02 (1H, dd, J = 16.0, 1.5Hz), 4.81-4.86 (1H, m), 4.02 (1H, dd, J = 9.0, 6.0 Hz), 3.86-3.91(1H, m), 3.73(3H, s), 3.46-3.52(2H, m), 2.87-2.94(1H, m), 2.51(1H, dd, J=14.0, 10.0Hz) , 2.14 (1H, dd, J=7.5, 5.5Hz), 1.92-1.98 (1H, m), 1.75-1.83 (1H, m), 1.66-1.74 (3H, m), 1.61-1.45 (1H, m) , 1.33 (3H, d, J=7.0Hz), 1.27-1.35 (1H, m)

¹³ CNMR (125MHz, CDCl ₃ )

δ166.95, 148.24, 123.08, 120.00, 84.03, 74.31, 74.25, 67.85, 67.77, 51.85, 40.23, 35.52, 26.80, 24.18, 22.27, 18.30

LRMS(ESI)m/z measured value 332.05[M+Na] ⁺

Example 9: Synthesis of Compound AO from Compound AN

Program 19

The reactor was charged with _PtO2 (0.73 wt%, 1.0 mol%) under _N2 . A solution of compound AN in MeOH (10.0 V) was added under _N2 . The resulting slurry was cooled to 15 °C and stirred under 1.04 bar _H2 . After 2 hours, the reaction was warmed to 20 °C and stirring was continued until compound AN was consumed completely. The reaction mixture was filtered through a pad of celite (1 Wt), and the filter cake was washed with MeOH (5.0 V). The filtrate was concentrated and residual MeOH was azeotroped off dry with DCM (3.0Vx2) to afford Compound AO as a gray oil (1.06Wt, 1.05eq). The crude product was used in the next reaction without purification.

¹ HNMR (500MHz, CDCl ₃ )

δ4.18-4.23 (1H, m), 3.82-3.91 (2H, m), 3.67 (3H, s), 3.53 (2H, d, J=6.5Hz), 2.86-2.93 (1H, m), 2.40- 2.46(1H, m), 2.31-2.38(2H, m), 2.17(1H, t, J=7.0Hz), 1.85-1.92(1H, m), 1.59-1.84(6H, m), 1.49(1H, dd, J=14.0, 5.5Hz), 1.32 (3H, d, J=7.5Hz), 1.23-1.30 (1H, m)

¹³ CNMR (125MHz, CDCl ₃ )

δ173.90, 123.10, 84.23, 74.90, 73.28, 68.31, 67.73, 51.81, 40.28, 35.99, 31.75, 30.78, 27.12, 24.03, 22.27, 18.32

LRMS(ESI)m/z measured value 334.08[M+Na] ⁺

Example 10: Synthesis of Compound AF from Compound AO

Program 20

Compound AO (1 Wt, 1 V, 1 eq) was dissolved in DCM (4.50 V). TEA (1.16V, 0.84Wt, 2.60eq) was added and the mixture was cooled to -70°C. A solution of _Tf2O (0.702 V, 1.30 eq) in DCM (1.50 V) was added at such a rate that the internal temperature did not exceed -65 °C. After the addition was complete, the reaction was stirred at -73°C for 1.5 hours, warmed to -20°C, and stirred at -20°C for an additional 30 minutes.

DMF (3.0 V) was added and the mixture was warmed to 0 °C. NaI (0.674Wt, 1.40eq) was added and the reaction was rewarmed to 23°C. After complete consumption of the triflate (compound AT), the reaction mixture was diluted with heptane (8.0 V) and cooled to 0°C. Water (9.0V) was added while maintaining the internal temperature below 10°C. The resulting biphasic mixture was stirred vigorously for 3 minutes then partitioned. The organic layer was set aside and the aqueous layer was extracted with MTBE (6.0V). All organic layers were combined and washed sequentially with: 1) 1.00MHClaq (5.00V, 1.56eq); 2) 10wt% NaHCO ₃ aq (2.0V); 3) 10wt% Na ₂ S ₂ O ₃ aq (2.0V) , 4) water (2.0V); 5) water (2.0V), concentrated. The residue was dissolved in MTBE (6.0V) and silica gel (1.0Wt) was added. The resulting slurry was stirred at 22°C for 5 minutes, then filtered. The silica gel on the filter was washed with MTBE (8.0V) and the filtrate was concentrated to give the crude product as a reddish solid (1.35Wt, 1.00eq).

Compound AF (1.35Wt, 1.00eq) was suspended in MTBE (1.4V) and heated to 45°C. Heptane (2.8V) was added while maintaining the internal temperature between 40°C and 45°C. The resulting clear solution was cooled to 22°C over 1 hour, then stirred at 22°C for 2 hours. The mixture was cooled to 0°C and stirring was continued for 2 hours. The precipitate was collected by filtration, washed with precooled (0 °C) heptane-MTBE (1:3 v/v, 2.8 V), and dried under _N2 /vacuum for 1 h to obtain compound AF as a light brown powder (0.98 Wt, 0.72eq). The mother liquor was concentrated and redissolved in MTBE (0.33V). Heptane (0.33V) was added and the resulting clear solution was cooled to 0°C. A very small amount of crystals of compound AF (from the first batch) was added as seed and stirring was continued at 0°C for 15 hours. The precipitate was collected by filtration, washed with pre-cooled (0°C) heptane-MTBE (1:2v/v, 0.33V), and dried under _N2 /vacuum for 1 hour to obtain compound AF as light brown powder (0.046Wt, 0.034eq).

Compound AT

¹ HNMR (500MHz, CDCl ₃ )

δ4.46 (1H, d, J = 10.5Hz), 4.38 (1H, d, J = 10.5Hz), 4.21-4.26 (1H, m), 3.89 (1H, dd, J = 8.5, 6.0Hz), 3.81 -3.86(1H, m), 3.68(3H, s), 2.93-3.00(1H, m), 2.41-2.50(2H, m), 2.33-2.39(1H, m), 1.91-1.97(1H, m) , 1.64-1.92 (6H, m), 1.45 (1H, dd, J = 14.5, 5.5Hz), 1.25-1.35 (1H, m), 1.32 (3H, d, J = 7.0Hz)

¹³ CNMR (125MHz, CDCl ₃ )

δ173.62, 122.86, 117.51, 81.84, 78.54, 74.57, 73.08, 68.63, 51.94, 40.16, 35.28, 31.77, 30.64, 27.13, 23.95, 22.33, 18.42

LRMS(ESI) m/z measured value 446.12[M+Na] ⁺

Compound AF

¹ HNMR (500MHz, CDCl ₃ )

δ4.21-4.26(1H, m), 3.78-3.83(2H, m), 3.67(3H, s), 3.44(1H, d, J=10.0Hz), 3.37(1H, d, J=10.0Hz) , 2.99-3.03 (1H, m), 2.49 (1H, dd, J=9.0, 8.5Hz), 2.42-2.47 (1H, m), 2.32-2.38 (1H, m), 1.80-1.89 (3H, m) , 1.63-1.75 (5H, m), 1.33 (3H, d, J=7.5Hz), 1.24-1.30 (1H, m)

¹³ CNMR (125MHz, CDCl ₃ )

δ173.74, 122.89, 81.75, 76.07, 75.10, 68.24, 51.86, 40.52, 39.00, 31.78, 30.75, 27.09, 24.36, 22.53, 18.72, 18.51

LRMS(ESI) m/z measured value 444.02[M+Na] ⁺

Melting point 69.5°C

Example 11: Synthesis of Compound AP from Compound AF

Scheme 21

Compound AF (1Wt, 1V, 1eq) was dissolved in toluene (5.0V) and cooled to 10°C. _LiBH4 (2.0M in THF, 2.4V, 2.0eq) was added and stirring was continued at 20°C for 18 hours. The reaction mixture was cooled to 0°C and poured slowly into a pre-cooled (0°C) mixture of EtOAc (6V) and 1.0M HClaq (6.0V, 2.5eq) with vigorous stirring. The reactor was rinsed with EtOAc (2V) and the resulting wash was combined with the biphasic mixture. The organic layer was set aside and the aqueous layer was extracted with EtOAc (5.0V). All organic layers were combined, washed sequentially with: 1) 10 wt% _NaHCO3aq (2V); 2) water (2V), and concentrated. Residual water was removed azeotropically with toluene (5Vx2) to give compound AP (0.93Wt, 0.89eq).

¹ HNMR (500MHz, CDCl ₃ )

δ4.24-4.30 (1H, m), 3.86 (1H, dd, J=8.5, 6.0Hz), 3.78-3.83 (1H, m), 3.62-3.68 (2H, m), 3.44 (1H, d, J =10.5Hz), 3.38(1H, d, J=10.5Hz), 2.99-3.04(1H, m), 2.51(1H, dd, J=14.0, 8.5Hz), 2.06(1H, t, J=6.0Hz ), 1.86-1.92 (1H, m), 1.59-1.78 (9H, m), 1.33 (3H, d, J=7.0Hz), 1.24-1.31 (1H, m)

¹³ CNMR (125MHz, CDCl ₃ )

δ122.94, 82.70, 76.27, 76.25, 68.42, 62.77, 40.50, 39.08, 33.72, 29.67, 27.25, 24.59, 22.55, 19.08, 18.51

LRMS(ESI) m/z measured value 416.02[M+Na] ⁺

Example 12: Synthesis of Compound AU from Compound AP

Scheme 22

Zn powder (2.5Wt, 15eq) was added to an inert reactor at 23°C. MeOH (5.0V) was added followed by AcOH (2.0V, 14eq). The resulting slurry was stirred at 23°C for 20 minutes, then cooled to 0°C. A solution of compound AP (1 Wt, 1 V, 1 eq) in MeOH (5.0 V) was added and vigorous stirring was continued at 0°C for 3 hours and at 23°C for 1.5 hours. The reaction mixture was diluted with EtOAc (20V). Excess Zn powder was removed by filtration, rinsed with EtOAc (10V). The filtrate was washed with 1.00M HClaq (10V). The organic layer was set aside and the aqueous layer was extracted with EtOAc (20V). All organic layers were combined and washed sequentially with: 1) 10 wt% _NaHCO3aq (20V); ₂ ) 10wt% _Na2S2O3aq (8V); ₃ ) brine (8V) and concentrated to give the crude product, It is light yellow oil. The crude product was purified by flash column chromatography (Biotage, Heptane-EtOAc 3:7→2:8→0:10) to give compound AU (0.62Wt, 0.90eq) as a pale yellow oil.

¹ HNMR (500MHz, CDCl ₃ )

δ5.01(1H, s), 4.85(1H, s), 4.41(1H, br), 4.08-4.12(1H, m), 3.93(1H, br), 3.60-3.68(2H, m), 3.12( 1H, br), 2.97-3.05(1H, m), 2.69-2.73(1H, m), 2.45(1H, br), 2.29-2.33(1H, m), 1.53-1.80(10H, m), 1.33( 3H, d, J=7.5Hz)

¹³ CNMR (125MHz, CDCl ₃ )

δ150.95, 123.29, 105.49, 79.66, 77.69, 68.79, 62.84, 41.83, 39.03, 34.33, 32.11, 30.89, 29.80, 22.93, 18.61

LRMS(ESI)m/z measured value 289.96[M+Na] ⁺

Example 13: Synthesis of Compound AR from Compound AU

Scheme 23

Compound AU (1Wt, 1V, 1eq) was dissolved in MeOH (2.0V). The mixture was cooled to 0°C and HCl (6M in IPA, 2.0V, 13eq) was added. The reaction was warmed to 23 °C and stirring was continued until complete consumption of compound AU (approximately 20 hours). The reaction mixture was diluted with toluene (8.0V) and water (4.0V) and the resulting biphasic mixture was heated at 60°C for 3 hours. After cooling, the organic layer was set aside and the aqueous layer was extracted with EtOAc (8.0 V). All organic layers were combined, washed sequentially with: 1) 10wt% NaHCO ₃ aq (2.0V); 2) brine (2.0V); 3) water (2.0V), concentrated to give crude compound AR (0.93Wt, 0.93 eq), as light yellow oil. The crude product was azeotropically dried with toluene (8Vx2) and used in the next reaction without purification.

¹ HNMR (500MHz, CDCl ₃ )

δ4.98-4.99(1H, m), 4.84-4.85(1H, m), 4.49-4.54(1H, m), 4.39(1H, d, J=10.5Hz), 4.00-4.05(1H, m), 3.59-3.68(2H,m), 2.63-2.72(2H,m), 2.56-2.62(1H,m), 2.25-2.30(1H,m), 2.08-2.14(1H,m), 1.97-2.02(1H , m), 1.52-1.82 (7H, m), 1.26 (3H, d, J=7.5Hz), 1.24-1.34 (1H, m)

¹³ CNMR (125MHz, CDCl ₃ )

δ180.34, 151.14, 105.39, 79.71, 78.84, 77.54, 62.72, 39.02, 35.69, 34.15, 32.19, 32.16, 31.50, 29.64, 16.02

LRMS(ESI)m/z measured value 290.99[M+Na] ⁺

Example 14: Synthesis of Compound AH from Compound AR

Scheme 24

Compound AR (1Wt, 1V, 1eq) was dissolved in DMF (2.0vols) and added (0.330Wt, 1.30eq) at 23°C (endotherm). After the imidazole was completely dissolved, the mixture was cooled to 10°C, and tert-butyldiphenylchlorosilane (TBDPSCl, 0.969V, 1.02Wt, 1.00eq) was added. The reaction mixture was stirred at 10° C. for 1 hour, warmed to 23° C., and stirred until compound AR was completely consumed (about 3 hours). The reaction mixture was diluted with heptane-MTBE 1:1 (8.0V) and cooled to 10°C. Water (8.0 V) was added with vigorous stirring and the resulting mixture was partitioned. Set aside the water layer. The organic layer was washed with water (1.0 V) and concentrated. Residual water and solvent were removed azeotropically with toluene (8.0Vx2) to afford compound AH as anhydrous oil (1.98Wt, 100%). The crude product was used in the next reaction without purification.

¹ HNMR (500MHz, CDCl ₃ )

δ7.65-7.67 (4H, m), 7.36-7.44 (6H, m), 4.99 (1H, dd, J = 4.0, 2.5Hz), 4.84 (1H, dd, J = 4.0, 2.5Hz), 4.50- 4.55(1H, m), 4.35(1H, d, J=9.0Hz), 3.97-4.02(1H, m), 3.66-3.70(2H, m), 2.66-2.71(1H, m), 2.61-2.66( 1H, m), 2.22-2.27 (1H, m), 2.08-2.14 (1H, m), 1.97-2.03 (1H, m), 1.50-1.81 (8H, m), 1.28 (3H, d, J=7.5 Hz), 1.04 (9H, s)

¹³ CNMR (125MHz, CDCl ₃ )

δ180.18, 151.68, 135.79(4C), 134.21(2C), 129.84(2C), 127.89(4C), 105.27, 79.58, 78.83, 77.38, 64.02, 39.08, 35.78, 34.20, 32.29, 31.76, 391.31, 27.16(3C), 19.48, 16.15

LRMS(ESI) m/z measured value 529.26[M+Na] ⁺

Example 15: Synthesis of Compound AV from Compound AH

Program 25

An inert reactor was charged with N,O-dimethylhydroxylamine hydrochloride (0.298 wt, 1.55 eq). DCM (2.0V) was added and the resulting slurry was cooled to -5°C. Trimethylaluminum (2.0 M in toluene, 1.48 V, 1.50 eq) was slowly added at such a rate that the internal temperature did not exceed 3°C. After the addition was complete, the mixture was stirred at 0°C for 30 minutes. A solution of Compound AH (1 Wt, 1 V, 1 eq) in DCM (3.0 V) was added at such a rate that the internal temperature did not exceed 5 °C and stirring was continued at 0 °C until complete consumption of Compound AH. Charge 20wt% Rochelle salt (10Wt) and MTBE (10V) into another reactor and cool to 0°C. The reaction mixture was transferred to a pre-cooled biphasic mixture while maintaining the internal temperature below 5 °C. The resulting mixture was stirred vigorously at 0°C for 30 minutes, then allowed to partition. The organic layer was set aside and the aqueous layer was extracted with MTBE (10V). All organic layers were combined, washed sequentially with 1) 20 wt% Rochelle salt solution (5Wt); 2) water (3V); 3) brine (2V), and concentrated to give the crude product as a light yellow oil. The crude product was azeotropically dried with toluene (5Vx2) and used in subsequent reactions without purification.

The crude hydroxyamide was dissolved in DMF (2.0V) and cooled to 10°C. Imidazole (0.161Wt, 1.20eq) was added followed by TBSCl (0.297Wt, 1.00eq). The reaction was stirred at 15°C for 2 hours, warmed to 23°C, and stirred until the hydroxyamide intermediate was consumed. The reaction mixture was diluted with heptane-MTBE 1:1 (10V) and cooled to 0°C. Water (8V) was added and the resulting biphasic mixture was stirred vigorously and allowed to partition. The organic layer was set aside, and the aqueous layer was extracted with heptane-MTBE (1:1 v/v, 8.0V). All organic layers were combined, washed sequentially with: 1) water (3.0V); 2) brine (3.0V), and concentrated to give crude compound AV (1.35Wt, 0.99eq) as a light yellow oil.

equivalent scheme

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. The contents of all references, patents, and patent applications cited in this application are hereby incorporated by reference. Appropriate components, processes and methods of those patents, applications and other documents can be selected for use in the present invention and its embodiments.

Claims (6)

1. formula (I) compound:

Wherein:

Z is double bond;

X ²for C;

X ¹for O;

L ¹for C ₁-C ₈alkyl-carbonyl; And

Y ¹for hydrogen; Or

Z is singly-bound;

X ²for CH or O;

X ¹for O;

Y ¹for halogen, hydrogen or O-L ², or work as X ²during for O, there is not Y ¹; With

L ¹for hydrogen or C ₁-C ₈alkyl-carbonyl;

L ²for hydrogen; Or

L ¹and L ²be cyclohexylidene together,

Condition is, works as Y ¹during for halogen, with the carbon of its combination, there is S configuration, and work as Y ¹for O-L ²time, with the carbon of its combination, there is R configuration.

2. the compound of claim 1, wherein L ¹for C ₁alkyl-carbonyl.

3. the compound of claim 1, wherein L ¹for C ₁-C ₈the carbonyl that alkyl replaces.

4. the compound of claim 1, wherein said compound is:

5. the compound of claim 1, wherein said formula (I) compound is formula (Ib):

Wherein L ^1afor hydrogen, and L ^1bhydrogen or blocking group as defined in claim 1, or L ^1aand L ^1bbe divalent protecting group group as defined in claim 1 together.

6. be selected from following compound: